Modular asymmetric total synthesis of bioactive multi-chiral natural products

Code:

Z1-2635

Range:

01. September 2020 - 31. August 2022

Range:

0,67 FTE

Leader:

Andrej Emanuel Cotman

Field:

1.04 Natural Sciences and mathematics/Chemistry

Research Organisation:

https://cris.cobiss.net/ecris/si/en/project/18398

Researchers:

https://cris.cobiss.net/ecris/si/en/project/18398

Content:

https://cris.cobiss.net/ecris/si/en/project/18398

Abstract:

Bioactive compounds featuring natural product-inspired three-dimensional molecular architectures exhibit higher rate of clinical success compared to synthetically less challenging flat aromatic drug candidates. Accessing such complex multi-chiral scaffolds is a daring task and is often precluded by the limitations of organic chemistry or avoided by medicinal chemists due to impracticality and limited reach of chemical space. The project addresses this scientific challenge by developing a conceptually new modular asymmetric total synthesis of natural products from the family of resveratrol dimers employing cutting-edge organometallic catalysis. Resveratrol, a naturally occurring polyphenol, serves as a precursor to a plethora of stilbenoid phytoanexins – plant defense compounds that accumulate rapidly at sites of pathogenesis.  Several resveratrol dimers, trimers and tetramers have been shown to exhibit biological activities beyond their natural role, including cytotoxic, estrogenic and antibacterial activity. Owing to their fascinating molecular architectures and intriguing biological activities, the resveratrol di- and oligomers have inspired a number of synthetic endeavors. Most synthetic approaches were biomimetic, relying on inherent redox reactivity of polyphenols, which limits the scope of accessible compounds to those, closely resembling the natural products. Moreover, no asymmetric total synthesis of indane- and dibenzopentalene-cored resveratrol oligomers with asymmetric catalysis in the key step has been reported. Our approach to this challenging class of elaborate molecules relies on our recent detailed study of stereochemical outcome in the reduction of indanones involving concomitant formation of up to four contiguous stereocenters. The key stereoconvergent step of the total synthesis will feature dynamic kinetic resolution accompanying ruthenium(II)-catalyzed asymmetric transfer hydrogenation and the synthetic route will allow up to four points of diversification within the same array of stereocenters. This type of catalysis is not sensitive to air and moisture, has a robust temperature and solvent range and is thus highly practical, transferable and scalable. Modular assembly of multi-chiral indane and dibenzopentalene scaffolds will enable the synthesis of structurally diverse natural product analogs for bioactivity and medicinal chemistry studies. Combined with in-house evaluation of biological activity the project offers an integrated approach to nature-inspired bioactive lead compounds. The postdoctoral researcher has experience and specific know-how in multi-step asymmetric synthesis and metal-catalyzed reaction development. Full support will be provided by the Chair of Pharmaceutical Chemistry at Faculty of Pharmacy, University of Ljubljana, which has complementary long-term experiences in design, synthesis and biological evaluation of bioactive leads. The combined expertise is a strong foundation for successful realization of this innovative project.

Phases:

The project aims are

a) to develop an efficient synthetic route to 6 representative resveratrol dimers (and their enantiomers) with an emphasis on optimization of stereo-convergent key synthetic step;
b) to confirm or reassign the absolute configurations of resveratrol dimers from natural sources;
c) to scale-up the synthesis, producing sufficient material for evaluation of biological activity;
d) to systematically evaluate biological activity of natural products and analogues;
e) to prepare non-natural analogs of resveratrol dimers, taking advantage of the modular synthetic route, allowing basic structure-activity relationship studies.

Bibliographical references, arising directly from the implementation of the project:

https://cris.cobiss.net/ecris/si/en/project/18398

Financed by:

Research projects (co)funded by the Slovenian Research Agency.